Our laboratory has a strong interest in pharmacogenetics. We have integrated pharmacogenetics/pharmacogenomics (PG) research in our drug development efforts to evaluate the impact of genetic variants on drug metabolism, PK, response and toxicity as well as to understand the contribution of inter-individual variation in clinical outcomes in therapies with an already narrow therapeutic window. We have established a molecular link between these polymorphisms and their phenotype as it relates to drug treatment. Most of our work has been focused on genetic variations in drug metabolism and transporting candidate genes such as ABCB1 (P-glycoprotein, MDR1), ABCG2 (BCRP), SLCO1B3 (OATP1B3, OATP8), CYP3A4, CYP3A5, CYP1B1, CYP2C19, CYP2D6, UGT1A1, UGT1A9 and several others. Drug transporters mediate the movement of endobiotics and xenobiotics across biological membranes in multiple organs and in most tissues. As such, they are involved in physiology, development of disease, drug pharmacokinetics, and ultimately the clinical response to a myriad of medications. Genetic variants in transporters cause population-specific differences in drug transport and are responsible for considerable interindividual variation in physiology and pharmacotherapy. Thus, we are interested in studying how inherited variants in transporters are associated with disease etiology, disease state, and the pharmacological treatment of diseases. We are also interested in non-candidate gene approaches where large numbers of polymorphisms are explored to establish a relationship with clinical outcome, and experiments are conducted to validate potential causative alleles resulting from exploratory scanning. We have worked with Affymetrix to beta-test the DMET chip that contains 1,936 genetic variations in 231 drug disposition genes, and have established a clinical trial where patients treated at the NCI will be genotyped with the DMET chip to explore potential links between these genes and outcomes from several cancer therapies. We are currently making progress in validating the results from the initial DMET chip experiments. While many of these studies have been conducted in order to explain some of the genetic influence on pharmacokinetic variability, we also have a strong interest in clarifying genetic markers of pharmacodynamics and therapeutic outcome of several major anticancer agents since this field has been rather poorly studied. We have studied the pharmacogenetics assessments of many anticancer agents including recently mithramycin, belinostat, docetaxel/lenalidomide/bevacizumab combination, olaparib/carboplatin combination, carfilzomib, azathioprine, and abiraterone. In our continuing collaborative effort with the University of Maryland, we were involved in conducting the pharmacogenomics studies on clopidogrel, one of the most commonly used therapeutics for the secondary prevention of cardiovascular events in patients with acute coronary syndromes. Considerable interindividual variation in clopidogrel response has been documented, resulting in suboptimal therapy and an increased risk of recurrent events for some patients. Evaluation of clopidogrel active metabolite concentration may help identify novel genetic determinants of clopidogrel response, which has implications for the development of novel therapeutics and improved antiplatelet treatment for at-risk patients in the future. We were involved with implementing the pharmacogenomics program at the NIH Clinical Center. In the first phase, we implemented genotyping for HLA-A and HLA-B gene variations with clinical decision support (CDS) for abacavir, carbamazepine, and allopurinol. In the second phase, we implemented genotyping for drug-metabolizing enzymes and transporters: SLCO1B1 for CDS of simvastatin and TPMT for CDS of mercaptopurine, azathioprine, and thioguanine. We recently published a review to describe the implementation process, which involves clinical, laboratory, informatics, and policy decisions pertinent to the NIH CC. We participated in a multicenter cohort of pediatric heart transplant (HT) recipients to determine the frequency of TPMT genetic variation and assessed whether azathioprine-treated recipients with TPMT variants were at increased risk of infection. The prevalence of TPMT variants was similar across racial/ethnic groups to what has been previously reported in non-pediatric HT populations. We found no association between variant alleles and infection in the first year after HT. Because clinically detected cytopenia could have prompted dose adjustment or cessation, we recommend future studies assess the relationship of genotype to leukopenia/neutropenia in the pediatric transplantation population.